Wednesday, 20 November 2013

Catecholamines and Autism

Source: Wikipedia

As I mentioned a few posts
back, it looks like endocrinology of the brain holds the key to treating autism
and indeed most other psychiatric and neurological conditions.

Today’s post is about one group
of hormones/neurotransmitters called catecholamines.Due to the inter-relationships between
hormones, neurotransmitters and electrolytes it is helpful to group them
together.Catecholamines include three
well known hormones: -epinephrine
(adrenaline), norepinephrine (noradrenaline) and dopamine.

For those of you that did chemistry at school, the reason
for the odd sounding name, catecholamines,
is that these hormones contain a benzene ring with two OHs attached.

Catecholamines are very important hormones and also form
the basis of several well-known drugs.In chemistry when you take molecule like a hormone and make a tiny
change to it, it then is referred to as an analogue (or an analog).Some successful
drugs are catecholamine analogs.

Dopamine

In the brain dopamine acts as a
neurotransmitter; it appears to several distinct functions, some better known
than others.

·It controls
the release of several hormones in the brain.This may be the most important role in autism.

Attention deficit hyperactivity disorder(ADHD) and restless legs syndrome (RLS)
are also believed to be associated with decreased dopamine activity.

Given that until recently
autism was sometimes diagnosed as childhood schizophrenia and ADHD is evidently
a case of autism-lite, it looks like dopamine plays a key role in Autism.

Dopamine does not cross the
blood brain barrier (BBB) and its function outside the brain appears to be
completely different.Dopamine exerts
its effects by binding to receptors on the surface of cells; so far 5 types of
receptors have been identified.

Dopamine in ADHD

In ADHD it appears that genetic
differences lead to altered dopaminergic neurotransmission.

This part of science is only just emerging, but for many years some of
the most effective therapeutic agents for ADHD have been psychostimulants such
as methylphenidate (Ritalin) and amphetamine, drugs
that increase both dopamine and norepinephrine levels in brain.

Very recently a study was published by Cambridge
University, which would appear to contradict all this:-

Professor Barbara Sahakian who led the
study at the BCNI said: “We feel these results are extremely important since
they show that people who have poor concentration improve with
methylphenidate(Ritalin) treatment whether they have a diagnosis of adult ADHD
or not. These novel findings demonstrate that poor performers, including
healthy volunteers, were helped by the treatment and this was related to
increases in dopamine in the brain in an area of the striatum called the caudate
nucleus.”

Professor Trevor Robbins, co-author and
Director of the BCNI, said: “These findings question the previously accepted
view of major abnormalities in dopamine function as the main cause of adult
ADHD patients. While the results show that Ritalin has a 'therapeutic' effect
to improve performance it does not appear to be related to fundamental
underlying impairments in the dopamine system in ADHD.”

I find all this quite odd.The researchers are surprised to find that
Ritalin helps people without ADHD concentrate better.Are they not aware that for many years
students and “cognitive enhancers” have been taking Ritalin to improve their
exam grades? These people do not have
ADHD. If the researchers spent half an
hour on Google, they could have saved a lot of money.

The study showed that Ritalin
helps you concentrate and it also showed that using a combination of positron
emission tomography (PET) and magnetic resonance imaging (MRI) to measure grey matter that in ADHD there are structural differences in the brain’s grey
matter.I wonder how this comes as a
surprise to anyone.

It looks like the ADHD researchers
in India are far more advanced than their Cambridge counterparts.

Affecting Dopamine Levels in the Brain

After synthesis, dopamine is transported from the cytosol into synaptic vesicles by the vesicular monoamine transporter 2 (VMAT2).
Dopamine is stored in and remains in these vesicles until an action potential occurs and causes the contents of the vesicles to be ejected into the synaptic cleft.

Once in the synapse, dopamine binds to and activates dopamine receptors.

After an action potential, the dopamine molecules quickly become unbound
from their receptors. They are then absorbed back into the presynaptic cell,
via reuptake mediated
either by the high-affinity dopamine transporter (DAT) or by
the low-affinity plasma membrane
monoamine transporter (PMAT). Once back in the cytosol, dopamine
is subsequently repackaged into vesicles by VMAT2, making it available for
future release.

All in all, Ritalin does not look
a good idea for children with ADHD or autism.

Epinephrine

Epinephrine is a hormone and
neurotransmitter that poorly crosses the blood brain barrier (BBB).

Regulation

The major physiologic triggers of adrenaline release centre upon stresses,
such as physical threat, excitement, noise, bright lights, and high ambient
temperature. All of these stimuli are processed in the CNS

Adrenocorticotropic hormone (ACTH) and
the sympathetic nervous system stimulate
the synthesis of adrenaline precursors by enhancing the activity of tyrosine hydroxylase and dopamine-β-hydroxylase, two key
enzymes involved in catecholamine synthesis ACTH also stimulates the adrenal
cortex to release cotisol, which increases the expression of PNMT in chromaffin cells, enhancing
adrenaline synthesis. This is most often done in response to stress. The
sympathetic nervous system, acting via splanchnic
nerves to the adrenal medulla, stimulates the release of adrenaline.
Acetylcholine released by preganglionic sympathetic fibers of these nerves acts
on nicotinic acetylcholine receptors, causing
cell depolarization and an influx
of calcium through voltage-gated calcium channels.
Calcium triggers the exocytosis of chromaffin granules and, thus, the release
of adrenaline (and noradrenaline) into the bloodstream]

Unlike many other hormones, adrenaline and the other catecholamines do not
exert negative feedback to down regulate their own synthesis. Their action is
terminated with reuptake into nerve terminal endings, some minute dilution, and
metabolism by MAO and catechol-O-methyl transferase.

Norepinephrine

Norepinephrine is a hormone and
neurotransmitter responsible for vigilant concentration.As a stress hormone, norepinephrine affects
parts of the brain, such as the amygdala, where attention and
responses are controlled. Norepinephrine also underlies the fight-or-flight response, along
with epinephrine, directly increasing heart,
triggering the release of glucose from energy stores. It increases the brain's oxygen supply.
Norepinephrine can also suppress neuroinflammation when released diffusely in the brain from the locus
coeruleus.

Norepinephrine is synthesied from dopamine.It is released from the adrenal medulla into
the blood as a hormone, and is also a neurotransmitter in the central nervous
system (CNS).The actions of norepinephrine are carried out
via the binding to adrenergic receptors.

Clinical uses

Norepinephrine may be used for the indications attention
deficit hyperactivity disorder (ADHD), depression, and hypotension.
Norepinephrine, as with other catecholamines, cannot cross the blood–brain
barrier, so drugs such as amphetamines are necessary to increase brain levels.

Attention-deficit/hyperactivity disorder

Norepinephrine, like dopamine, has come to be recognized as playing a large
role in attention. For people with ADHD, psychostimulant medications such as amphetamines (Adderall, Desoxyn,) are
prescribed to increase both levels of norepinephrine and dopamine. Methylphenidate
(Ritalin/Concerta), a dopamine reuptake inhibitor, and Atomoxetine
(Strattera), a selective
norepinephrine reuptake inhibitor (SNRI), increase
both norepinephrine and dopamine in the prefrontal cortex equally but only
dopamine and norepinephrine, respectively, elsewhere in other parts of the
brain. Other SNRIs, currently approved as antidepressants, have also been used
off-label for treatment of ADHD

Depression

Differences in the norepinephrine system are implicated in depression. Serotonin-norepinephrine
reuptake inhibitors are antidepressants that treat depression by
increasing the amount of serotonin and norepinephrine available to cells in the
brain. There is some recent evidence implying that SNRIs may also
increase dopamine transmission. This is because SNRIs work by inhibiting
reuptake, i.e. inhibiting the serotonin and norepinephrine transporters from
taking their respective neurotransmitters back to their storage vesicles for
later use. If the norepinephrine normally recycles some dopamine too, then
SNRIs will also enhance dopamine transmission. Therefore, the antidepressant
effects associated with increasing norepinephrine levels may also be partly or
largely due to the concurrent increase in dopamine.

Tricyclic antidepressants (TCAs)
increase norepinephrine activity
as well. Most of them also increase serotonin activity, but tend to produce
unwanted side-effects due to the nonspecific inactivation of histamine,
acetylcholine and alpha-1 adrenergic receptors. Common side-effects include
sedation, dry mouth, constipation, sinus tachycardia, memory impairment,
orthostatic hypotension, blurred vision, and weight gain. For this reason, they have largely been
replaced by newer selective reuptake drugs. These include the SSRIs, e.g. fluoxetine (Prozac),
which however have little or no effect on norepinephrine, and the newer SNRIs, such as venlafaxine (Effexor)
and duloxetine (Cymbalta).

Anti-inflammatory agent role in Alzheimer’s
disease

The norepinephrine from locus ceruleus cells in addition to its
neurotransmitter role locally diffuses from "varicosities". As such,
it provides an endogenous anti-inflammatory agent in the microenvironment around
the neurons, glial cells, and blood
vessels in the neocortex and hippocampus. Up to 70% of norepinephrine
projecting cells are lost in Alzheimer’s disease.

Timothy Syndrome

Timothy Syndrome is a rare genetic
condition that is generally accompanied by autism.Researchers at Stanford University found that
this type of autism is caused by defective calcium channels in thebrain and that the defect could be reversed
witha drug.Note that in this syndrome there is OVER-production ofdopamine and norepinephrine.

In this study, the scientists suggest that the autism in Timothy syndrome
patients is caused by a gene mutation that makes calcium channels in neuron
membranes defective, interfering with how those neurons communicate and
develop. The flow of calcium into neurons enables them to fire, and the way that
the calcium flow is regulated is a pivotal factor in how our brains function.

The researchers also found brain cells grown from individuals with Timothy
syndrome resulted in fewer of the kind of cells that connect both halves of the
brain, as well as an overproduction of two of the brain’s chemical messengers,
dopamine and norepinephrine. Furthermore, they found they could reverse these
effects by chemically blocking the faulty channels.

Conclusion

This post was a short biology
lesson.Its relevance will become
apparent in later posts as we look at the inter-relationships between
hormones/neurotransmitters and ion channels/transporters.

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